Displaying publications 1 - 20 of 37 in total

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  1. Iliotibial band tension affects patellofemoral and tibiofemoral kinematics
    Merican AM, Amis AA
    J Biomech, 2009 Jul 22;42(10):1539-1546.
    PMID: 19481211 DOI: 10.1016/j.jbiomech.2009.03.041
    The iliotibial band (ITB) has an important role in knee mechanics and tightness can cause patellofemoral maltracking. This study investigated the effects of increasing ITB tension on knee kinematics. Nine fresh-frozen cadaveric knees had the components of the quadriceps loaded with 175 N. A Polaris optical tracking system was used to acquire joint kinematics during extension from 100 degrees to 0 degrees flexion. This was repeated after the following ITB loads: 30, 60 and 90 N. There was no change with 30 N load for patellar translation. On average, at 60 and 90 N, the patella translated laterally by 0.8 and 1.4mm in the mid flexion range compared to the ITB unloaded condition. The patella became more laterally tilted with increasing ITB loads by 0.7 degrees, 1.2 degrees and 1.5 degrees for 30, 60 and 90 N, respectively. There were comparable increases in patellar lateral rotation (distal patella moves laterally) towards the end of the flexion cycle. Increased external rotation of the tibia occurred from early flexion onwards and was maximal between 60 degrees and 75 degrees flexion. The increase was 5.2 degrees, 9.5 degrees and 13 degrees in this range for 30, 60 and 90 N, respectively. Increased tibial abduction with ITB loads was not observed. The combination of increased patellar lateral translation and tilt suggests increased lateral cartilage pressure. Additionally, the increased tibial external rotation would increase the Q angle. The clinical consequences and their relationship to lateral retinacular releases may be examined, now that the effects of a tight ITB are known.
  2. Fulltext Iliotibial band tension reduces patellar lateral stability
    Merican AM, Iranpour F, Amis AA
    J Orthop Res, 2009 Mar;27(3):335-9.
    PMID: 18925647 DOI: 10.1002/jor.20756
    This study investigated the effect of loading the iliotibial band (ITB) on the stability of the patellofemoral joint. We measured the restraining force required to displace the patella 10 mm medially and laterally (defined as medial and lateral stability, respectively) in 14 fresh-frozen knees from 0 to 90 degrees knee flexion. The testing rig allowed the patella to rotate and translate freely during this displacement. The quadriceps was separated into five components and loaded with 175 N total tension. Testing was performed at 0 to 90 N ITB tension. With no ITB tension, the lateral restraining force ranged from 82 to 101 N across 0 to 90 degrees flexion. Increasing ITB tension caused progressive reduction of the lateral restraining force. The maximum reduction was 25% at 60 degrees flexion and 90 N ITB tension. Medial restraining force increased progressively with increasing knee flexion and increasing ITB loads; it ranged from 74 N at 0 degrees knee flexion and 0 N ITB tension to 211 N at 90 degrees knee flexion and 90 N ITB tension. The maximum effect was an increase of medial restraining force of 50% at 90 degrees flexion and 90 N ITB tension.
  3. Fulltext Searching for the Haplorrhine Heterotherm: Field and Laboratory Data of Free-Ranging Tarsiers
    Welman S, Tuen AA, Lovegrove BG
    Front Physiol, 2017;8:745.
    PMID: 29018365 DOI: 10.3389/fphys.2017.00745
    The observation of heterothermy in a single suborder (Strepsirrhini) only within the primates is puzzling. Given that the placental-mammal ancestor was likely a heterotherm, we explored the potential for heterothermy in a primate closely related to the Strepsirrhini. Based upon phylogeny, body size and habitat stability since the Late Eocene, we selected western tarsiers (Cephalopachus bancanus) from the island of Borneo. Being the sister clade to Strepsirrhini and basal in Haplorrhini (monkeys and apes), we hypothesized that C. bancanus might have retained the heterothermic capacity observed in several small strepsirrhines. We measured resting metabolic rate, subcutaneous temperature, evaporative water loss and the percentage of heat dissipated through evaporation, at ambient temperatures between 22 and 35°C in fresh-caught wild animals (126.1 ± 2.4 g). We also measured core body temperatures in free-ranging animals. The thermoneutral zone was 25-30°C and the basal metabolic rate was 3.52 ± 0.06 W.kg-1 (0.65 ± 0.01 ml O2.g-1.h-1). There was no evidence of adaptive heterothermy in either the laboratory data or the free-ranging data. Instead, animals appeared to be cold sensitive (Tb ~ 31°C) at the lowest temperatures. We discuss possible reasons for the apparent lack of heterothermy in tarsiers, and identify putative heterotherms within Platyrrhini. We also document our concern for the vulnerability of C. bancanus to future temperature increases associated with global warming.
  4. Biomechanical analysis of knee laxity with isolated anteromedial or posterolateral bundle-deficient anterior cruciate ligament
    Kondo E, Merican AM, Yasuda K, Amis AA
    Arthroscopy, 2014 Mar;30(3):335-43.
    PMID: 24581258 DOI: 10.1016/j.arthro.2013.12.003
    The purpose of this study was to clarify the changes in the kinematics of the knee that result from isolated deficiency of the anteromedial (AM) or posterolateral (PL) bundle.
  5. Quantitative Flow Cytometry-Based Assays for Measuring Constitutive Secretion
    Gordon DE, Shun-Shion AS, Asnawi AW, Peden AA
    Methods Mol Biol, 2021;2233:115-129.
    PMID: 33222131 DOI: 10.1007/978-1-0716-1044-2_8
    Constitutive secretion is predominantly measured by collecting the media from cells and performing plate-based assays. This approach is particularly sensitive to changes in cell number, and a significant amount of effort has to be spent to overcome this. We have developed a panel of quantitative flow cytometry-based assays and reporter cell lines that can be used to measure constitutive secretion. These assays are insensitive to changes in cell number making them very robust and well suited to functional genomic and chemical screens. Here, we outline the key steps involved in generating and using these assays for studying constitutive secretion.
  6. Innate Immune and Neuronal Genetic Markers Are Highly Predictive of Postoperative Pain and Morphine Patient-Controlled Analgesia Requirements in Indian but Not Chinese or Malay Hysterectomy Patients
    Barratt DT, Sia AT, Tan EC, Somogyi AA
    Pain Med, 2021 Nov 26;22(11):2648-2660.
    PMID: 34015137 DOI: 10.1093/pm/pnab172
    OBJECTIVE: Pain severity and opioid requirements in the postoperative period show substantial and clinically significant inter-patient variation due mainly to factors such as age, surgery type, and duration. Genetic factors have not been adequately assessed except for the neuronal OPRM1 rs1799971 and COMT rs4680, whereas the contribution of innate immune signaling pathway genetics has seldom been investigated.

    SETTING: Hospital surgical ward.

    SUBJECTS: Women (107 Indian, 184 Malay, and 750 Han Chinese) undergoing total hysterectomy surgery.

    METHODS: Morphine consumption, preoperative pain, and postoperative pain were evaluated in relation to genetic variability comprising 19 single-nucleotide polymorphisms (SNPs) in 14 genes involved in glial activation, inflammatory signaling, and neuronal regulation, plus OPRM1 (1 SNP) and COMT (3 SNPs).

    RESULTS: Pre- and postoperative pain and age were associated with increased and decreased morphine consumption, respectively. In Chinese patients, only 8% of the variability in consumption could be explained by these nongenetic and genetic (BDNF, IL1B, IL6R, CRP, OPRM1, COMT, MYD88) factors. However, in Indian patients, 41% of morphine consumption variability could be explained by age (explaining <3%) and variants in OPRM1 rs1799971, CRP rs2794521, TLR4 rs4986790, IL2 rs2069762, COMT rs4818, TGFB1 rs1800469, and IL6R rs8192284 without controlling for postoperative pain.

    CONCLUSIONS: This is the highest known value reported for genetic contributions (38%) to morphine use in the acute postoperative pain setting. Our findings highlight the need to incorporate both genetic and nongenetic factors and consider ethnicity-dependent and nonadditive genotypic models in the assessment of factors that contribute to variability in opioid use.

  7. A national survey of renal replacement therapy prescribing practice for acute kidney injury in Malaysian intensive care units
    Jamal JA, Mat-Nor MB, Mohamad-Nor FS, Udy AA, Lipman J, Roberts JA
    Nephrology (Carlton), 2014 Aug;19(8):507-12.
    PMID: 24802363 DOI: 10.1111/nep.12276
    To describe renal replacement therapy (RRT) prescribing practices in Malaysian intensive care units (ICU), and compare this with previously published data from other regions.
  8. Patellar thickness and lateral retinacular release affects patellofemoral kinematics in total knee arthroplasty
    Merican AM, Ghosh KM, Baena FR, Deehan DJ, Amis AA
    Knee Surg Sports Traumatol Arthrosc, 2014 Mar;22(3):526-33.
    PMID: 23271038 DOI: 10.1007/s00167-012-2312-z
    PURPOSE: To study the effect of increasing patellar thickness (overstuffing) on patellofemoral kinematics in total knee arthroplasty and whether subsequent lateral retinacular release would restore the change in kinematics.

    METHODS: The quadriceps of eight fresh-frozen knees were loaded on a custom-made jig. Kinematic data were recorded using an optical tracking device for the native knee, following total knee arthroplasty (TKA), then with patellar thicknesses from -2 to +4 mm, during knee extension motion. Staged lateral retinacular releases were performed to examine the restoration of normal patellar kinematics.

    RESULTS: Compared to the native knee, TKA led to significant changes in patellofemoral kinematics, with significant increases in lateral shift, tilt and rotation. When patellar composite thickness was increased, the patella tilted further laterally. Lateral release partly corrected this lateral tilt but caused abnormal tibial external rotation. With complete release of the lateral retinaculum and capsule, the patella with an increased thickness of 4 mm remained more laterally tilted compared to the TKA with normal patellar thickness between 45° and 55° knee flexion and from 75° onwards. This was on average by 2.4° ± 2.9° (p 

  9. Fulltext Ion channels, long QT syndrome and arrhythmogenesis in ageing
    Jeevaratnam K, Chadda KR, Salvage SC, Valli H, Ahmad S, Grace AA, et al.
    Clin Exp Pharmacol Physiol, 2017 12;44 Suppl 1:38-45.
    PMID: 28024120 DOI: 10.1111/1440-1681.12721
    Ageing is associated with increased prevalences of both atrial and ventricular arrhythmias, reflecting disruption of the normal sequence of ion channel activation and inactivation generating the propagated cardiac action potential. Experimental models with specific ion channel genetic modifications have helped clarify the interacting functional roles of ion channels and how their dysregulation contributes to arrhythmogenic processes at the cellular and systems level. They have also investigated interactions between these ion channel abnormalities and age-related processes in producing arrhythmic tendency. Previous reviews have explored the relationships between age and loss-of-function Nav 1.5 mutations in producing arrhythmogenicity. The present review now explores complementary relationships arising from gain-of-function Nav 1.5 mutations associated with long QT3 (LQTS3). LQTS3 patients show increased risks of life-threatening ventricular arrhythmias, particularly after 40 years of age, consistent with such interactions between the ion channel abnormailities and ageing. In turn clinical evidence suggests that ageing is accompanied by structural, particularly fibrotic, as well as electrophysiological change. These abnormalities may result from biochemical changes producing low-grade inflammation resulting from increased production of reactive oxygen species and superoxide. Experimental studies offer further insights into the underlying mechanisms underlying these phenotypes. Thus, studies in genetically modified murine models for LQTS implicated action potential recovery processes in arrhythmogenesis resulting from functional ion channel abnormalities. In addition, ageing wild type (WT) murine models demonstrated both ion channel alterations and fibrotic changes with ageing. Murine models then suggested evidence for interactions between ageing and ion channel mutations and provided insights into potential arrhythmic mechanisms inviting future exploration.
  10. Fulltext Age-dependent electrocardiographic changes in Pgc-1β deficient murine hearts
    Ahmad S, Valli H, Salvage SC, Grace AA, Jeevaratnam K, Huang CL
    Clin Exp Pharmacol Physiol, 2018 02;45(2):174-186.
    PMID: 28949414 DOI: 10.1111/1440-1681.12863
    Increasing evidence implicates chronic energetic dysfunction in human cardiac arrhythmias. Mitochondrial impairment through Pgc-1β knockout is known to produce a murine arrhythmic phenotype. However, the cumulative effect of this with advancing age and its electrocardiographic basis have not been previously studied. Young (12-16 weeks) and aged (>52 weeks), wild type (WT) (n = 5 and 8) and Pgc-1β-/- (n = 9 and 6), mice were anaesthetised and used for electrocardiographic (ECG) recordings. Time intervals separating successive ECG deflections were analysed for differences between groups before and after β1-adrenergic (intraperitoneal dobutamine 3 mg/kg) challenge. Heart rates before dobutamine challenge were indistinguishable between groups. The Pgc-1β-/- genotype however displayed compromised nodal function in response to adrenergic challenge. This manifested as an impaired heart rate response suggesting a functional defect at the level of the sino-atrial node, and a negative dromotropic response suggesting an atrioventricular conduction defect. Incidences of the latter were most pronounced in the aged Pgc-1β-/- mice. Moreover, Pgc-1β-/- mice displayed electrocardiographic features consistent with the existence of a pro-arrhythmic substrate. Firstly, ventricular activation was prolonged in these mice consistent with slowed action potential conduction and is reported here for the first time. Additionally, Pgc-1β-/- mice had shorter repolarisation intervals. These were likely attributable to altered K+ conductance properties, ultimately resulting in a shortened QTc interval, which is also known to be associated with increased arrhythmic risk. ECG analysis thus yielded electrophysiological findings bearing on potential arrhythmogenicity in intact Pgc-1β-/- systems in widespread cardiac regions.
  11. Fulltext Femoral articular geometry and patellofemoral stability
    Iranpour F, Merican AM, Teo SH, Cobb JP, Amis AA
    Knee, 2017 Jun;24(3):555-563.
    PMID: 28330756 DOI: 10.1016/j.knee.2017.01.011
    BACKGROUND: Patellofemoral instability is a major cause of anterior knee pain. The aim of this study was to examine how the medial and lateral stability of the patellofemoral joint in the normal knee changes with knee flexion and measure its relationship to differences in femoral trochlear geometry.

    METHODS: Twelve fresh-frozen cadaveric knees were used. Five components of the quadriceps and the iliotibial band were loaded physiologically with 175N and 30N, respectively. The force required to displace the patella 10mm laterally and medially at 0°, 20°, 30°, 60° and 90° knee flexion was measured. Patellofemoral contact points at these knee flexion angles were marked. The trochlea cartilage geometry at these flexion angles was visualized by Computed Tomography imaging of the femora in air with no overlying tissue. The sulcus, medial and lateral facet angles were measured. The facet angles were measured relative to the posterior condylar datum.

    RESULTS: The lateral facet slope decreased progressively with flexion from 23°±3° (mean±S.D.) at 0° to 17±5° at 90°. While the medial facet angle increased progressively from 8°±8° to 36°±9° between 0° and 90°. Patellar lateral stability varied from 96±22N at 0°, to 77±23N at 20°, then to 101±27N at 90° knee flexion. Medial stability varied from 74±20N at 0° to 170±21N at 90°. There were significant correlations between the sulcus angle and the medial facet angle with medial stability (r=0.78, p<0.0001).

    CONCLUSIONS: These results provide objective evidence relating the changes of femoral profile geometry with knee flexion to patellofemoral stability.

  12. Fulltext Effects of ageing on pro-arrhythmic ventricular phenotypes in incrementally paced murine Pgc-1β -/- hearts
    Ahmad S, Valli H, Edling CE, Grace AA, Jeevaratnam K, Huang CL
    Pflugers Arch., 2017 Dec;469(12):1579-1590.
    PMID: 28821956 DOI: 10.1007/s00424-017-2054-3
    A range of chronic clinical conditions accompany cardiomyocyte energetic dysfunction and constitute independent risk factors for cardiac arrhythmia. We investigated pro-arrhythmic and arrhythmic phenotypes in energetically deficient C57BL mice with genetic ablation of the mitochondrial promoter peroxisome proliferator-activated receptor-γ coactivator-1β (Pgc-1β), a known model of ventricular arrhythmia. Pro-arrhythmic and cellular action potential (AP) characteristics were compared in intact Langendorff-perfused hearts from young (12-16 week) and aged (> 52 week), wild-type (WT) and Pgc-1β -/- mice. Simultaneous electrocardiographic and intracellular microelectrode recordings were made through successive trains of 100 regular stimuli at progressively incremented heart rates. Aged Pgc-1β -/- hearts displayed an increased incidence of arrhythmia compared to other groups. Young and aged Pgc-1β -/- hearts showed higher incidences of alternans in both AP activation (maximum AP upshoot velocity (dV/dt)max and latency), recovery (action potential duration (APD90) and resting membrane potential (RMP) characteristics compared to WT hearts. This was particularly apparent at lower pacing frequencies. These findings accompanied reduced (dV/dt)max and increased AP latency values in the Pgc-1β -/- hearts. APs observed prior to termination of the protocol showed lower (dV/dt)max and longer AP latencies, but indistinguishable APD90 and RMPs in arrhythmic compared to those in non-arrhythmic hearts. APD restitution analysis showed that Pgc-1β -/- and WT hearts showed similar limiting gradients. However, Pgc-1β -/- hearts had shortened plateau AP wavelengths, particularly in aged Pgc-1β -/- hearts. Pgc-1β -/- hearts therefore show pro-arrhythmic instabilities attributable to altered AP conduction and activation rather than recovery characteristics.
  13. Unheard voices of global surgery - trauma services in sub-Saharan Africa: a correspondence
    Mehta A, Wireko AA, Ohenewaa Tenkorang P, Ng JC, Rahman TA, Sikora V, et al.
    Int J Surg, 2023 Mar 01;109(3):521-522.
    PMID: 36906789 DOI: 10.1097/JS9.0000000000000145
  14. Fulltext Calling for continuous surgical support in Ukraine
    Wireko AA, Ng JC, David L, Abdul-Rahman T, Sikora V, Isik A
    Int J Surg, 2023 Apr 10;110(1):571-3.
    PMID: 37026787 DOI: 10.1097/JS9.0000000000000000
  15. Fulltext Tree shrew lavatories: a novel nitrogen sequestration strategy in a tropical pitcher plant
    Clarke CM, Bauer U, Lee CC, Tuen AA, Rembold K, Moran JA
    Biol Lett, 2009 Oct 23;5(5):632-5.
    PMID: 19515656 DOI: 10.1098/rsbl.2009.0311
    Nepenthes pitcher plants are typically carnivorous, producing pitchers with varying combinations of epicuticular wax crystals, viscoelastic fluids and slippery peristomes to trap arthropod prey, especially ants. However, ant densities are low in tropical montane habitats, thereby limiting the potential benefits of the carnivorous syndrome. Nepenthes lowii, a montane species from Borneo, produces two types of pitchers that differ greatly in form and function. Pitchers produced by immature plants conform to the 'typical' Nepenthes pattern, catching arthropod prey. However, pitchers produced by mature N. lowii plants lack the features associated with carnivory and are instead visited by tree shrews, which defaecate into them after feeding on exudates that accumulate on the pitcher lid. We tested the hypothesis that tree shrew faeces represent a significant nitrogen (N) source for N. lowii, finding that it accounts for between 57 and 100 per cent of foliar N in mature N. lowii plants. Thus, N. lowii employs a diversified N sequestration strategy, gaining access to a N source that is not available to sympatric congeners. The interaction between N. lowii and tree shrews appears to be a mutualism based on the exchange of food sources that are scarce in their montane habitat.
  16. Fulltext Antibodies to henipavirus or henipa-like viruses in domestic pigs in Ghana, West Africa
    Hayman DT, Wang LF, Barr J, Baker KS, Suu-Ire R, Broder CC, et al.
    PLoS One, 2011;6(9):e25256.
    PMID: 21966471 DOI: 10.1371/journal.pone.0025256
    Henipaviruses, Hendra virus (HeV) and Nipah virus (NiV), have Pteropid bats as their known natural reservoirs. Antibodies against henipaviruses have been found in Eidolon helvum, an old world fruit bat species, and henipavirus-like nucleic acid has been detected in faecal samples from E. helvum in Ghana. The initial outbreak of NiV in Malaysia led to over 265 human encephalitis cases, including 105 deaths, with infected pigs acting as amplifier hosts for NiV during the outbreak. We detected non-neutralizing antibodies against viruses of the genus Henipavirus in approximately 5% of pig sera (N = 97) tested in Ghana, but not in a small sample of other domestic species sampled under a E. helvum roost. Although we did not detect neutralizing antibody, our results suggest prior exposure of the Ghana pig population to henipavirus(es). Because a wide diversity of henipavirus-like nucleic acid sequences have been found in Ghanaian E. helvum, we hypothesise that these pigs might have been infected by henipavirus(es) sufficiently divergent enough from HeVor NiV to produce cross-reactive, but not cross-neutralizing antibodies to HeV or NiV.
  17. Fulltext S-acylation regulates the trafficking and stability of the unconventional Q-SNARE STX19
    Ampah KK, Greaves J, Shun-Shion AS, Asnawi AW, Lidster JA, Chamberlain LH, et al.
    J Cell Sci, 2018 10 22;131(20).
    PMID: 30254024 DOI: 10.1242/jcs.212498
    STX19 is an unusual Qa-SNARE as it lacks a C-terminal transmembrane domain. However, it is efficiently targeted to post-Golgi membranes. Here, we set out to determine the intracellular localisation of endogenous STX19 and elucidate the mechanism by which it is targeted to membranes. We have found that a pool of STX19 is localised to tubular recycling endosomes where it colocalises with MICAL-L1 and Rab8 (which has Rab8a and Rab8b forms). Using a combination of genetic, biochemical and cell-based approaches, we have identified that STX19 is S-acylated at its C-terminus and is a substrate for several Golgi-localised S-acyltransferases, suggesting that STX19 is initially S-acylated at the Golgi before trafficking to the plasma membrane and endosomes. Surprisingly, we have found that S-acylation is a key determinant in targeting STX19 to tubular recycling endosomes, suggesting that S-acylation may play a general role in directing proteins to this compartment. In addition, S-acylation also protects STX19 from proteosomal degradation, indicating that S-acylation regulates the function of STX19 at multiple levels.This article has an associated First Person interview with the first author of the paper.
  18. Fulltext Epac-induced ryanodine receptor type 2 activation inhibits sodium currents in atrial and ventricular murine cardiomyocytes
    Valli H, Ahmad S, Sriharan S, Dean LD, Grace AA, Jeevaratnam K, et al.
    Clin Exp Pharmacol Physiol, 2018 03;45(3):278-292.
    PMID: 29027245 DOI: 10.1111/1440-1681.12870
    Acute RyR2 activation by exchange protein directly activated by cAMP (Epac) reversibly perturbs myocyte Ca2+ homeostasis, slows myocardial action potential conduction, and exerts pro-arrhythmic effects. Loose patch-clamp studies, preserving in vivo extracellular and intracellular conditions, investigated Na+ current in intact cardiomyocytes in murine atrial and ventricular preparations following Epac activation. Depolarising steps to varying test voltages activated typical voltage-dependent Na+ currents. Plots of peak current against depolarisation from resting potential gave pretreatment maximum atrial and ventricular currents of -20.23 ± 1.48 (17) and -29.8 ± 2.4 (10) pA/μm2 (mean ± SEM [n]). Challenge by 8-CPT (1 μmol/L) reduced these currents to -11.21 ± 0.91 (12) (P  .05). Assessment of the inactivation that followed by applying subsequent steps to a fixed voltage 100 mV positive to resting potential gave concordant results. Half-maximal inactivation voltages and steepness factors, and time constants for Na+ current recovery from inactivation in double-pulse experiments, were similar through all the pharmacological conditions. Intracellular sharp microelectrode membrane potential recordings in intact Langendorff-perfused preparations demonstrated concordant variations in maximum rates of atrial and ventricular action potential upstroke, (dV/dt)max . We thus demonstrate an acute, reversible, Na+ channel inhibition offering a possible mechanism for previously reported pro-arrhythmic slowing of AP propagation following modifications of Ca2+ homeostasis, complementing earlier findings from chronic alterations in Ca2+ homeostasis in genetically-modified RyR2-P2328S hearts.
  19. Fulltext Age-dependent atrial arrhythmic phenotype secondary to mitochondrial dysfunction in Pgc-1β deficient murine hearts
    Valli H, Ahmad S, Chadda KR, Al-Hadithi ABAK, Grace AA, Jeevaratnam K, et al.
    Mech Ageing Dev, 2017 Oct;167:30-45.
    PMID: 28919427 DOI: 10.1016/j.mad.2017.09.002
    INTRODUCTION: Ageing and several age-related chronic conditions including obesity, insulin resistance and hypertension are associated with mitochondrial dysfunction and represent independent risk factors for atrial fibrillation (AF).

    MATERIALS AND METHODS: Atrial arrhythmogenesis was investigated in Langendorff-perfused young (3-4 month) and aged (>12 month), wild type (WT) and peroxisome proliferator activated receptor-γ coactivator-1β deficient (Pgc-1β-/-) murine hearts modeling age-dependent chronic mitochondrial dysfunction during regular pacing and programmed electrical stimulation (PES).

    RESULTS AND DISCUSSION: The Pgc-1β-/- genotype was associated with a pro-arrhythmic phenotype progressing with age. Young and aged Pgc-1β-/- hearts showed compromised maximum action potential (AP) depolarization rates, (dV/dt)max, prolonged AP latencies reflecting slowed action potential (AP) conduction, similar effective refractory periods and baseline action potential durations (APD90) but shortened APD90 in APs in response to extrasystolic stimuli at short stimulation intervals. Electrical properties of APs triggering arrhythmia were similar in WT and Pgc-1β-/- hearts. Pgc-1β-/- hearts showed accelerated age-dependent fibrotic change relative to WT, with young Pgc-1β-/- hearts displaying similar fibrotic change as aged WT, and aged Pgc-1β-/- hearts the greatest fibrotic change. Mitochondrial deficits thus result in an arrhythmic substrate, through slowed AP conduction and altered repolarisation characteristics, arising from alterations in electrophysiological properties and accelerated structural change.

  20. Fulltext Ageing in Pgc-1β-/- mice modelling mitochondrial dysfunction induces differential expression of a range of genes regulating ventricular electrophysiology
    Edling CE, Fazmin IT, Chadda KR, Ahmad S, Valli H, Grace AA, et al.
    Biosci Rep, 2019 04 30;39(4).
    PMID: 30914453 DOI: 10.1042/BSR20190127
    Mice deficient in mitochondrial promoter peroxisome proliferator activated receptor-γ co-activator-1β (Pgc-1β-/- ) is a valuable model for metabolic diseases and has been found to present with several pathologies including ventricular arrhythmia. In the present study, our aim was to shed light on the molecular mechanisms behind the observed arrhythmic substrate by studying how the expression of selected genes critical for cardiac function differs in wild-type (WT) compared with Pgc-1β knockout mice and young compared with aged mice. We found that a clear majority of genes are down-regulated in the Pgc-1β-/- ventricular tissue compared with the WT. Although most individual genes are not significantly differentially expressed, a pattern is apparent when the genes are grouped according to their functional properties. Genes encoding proteins relating to ATPase activity, potassium ion channels relating to repolarisation and resting membrane potential, and genes encoding proteins in the cAMP pathway are found to be significantly down-regulated in the Pgc-1β deficient mice. On the contrary, the pacemaker channel genes Hcn3 and Hcn4 are up-regulated in subsets of the Pgc-1β deficient tissue. Furthermore, we found that with age, especially in the Pgc-1β-/- genotype, most genes are up-regulated including genes relating to the resting membrane potential, calcium homeostasis, the cAMP pathway, and most of the tested adrenoceptors. In conclusion, we here demonstrate how a complex pattern of many modest changes at gene level may explain major functional differences of the action potential related to ageing and mitochondrial dysfunction.
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